Regulation of magnesium reabsorption in DCT.
The distal convoluted tubule (DCT) is the shortest segment of the nephron and consists of an early (DCT1) and late part (DCT2). Here, several transport proteins, like the thiazide-sensitive NaCl cotransporter (NCC) and the epithelial magnesium (Mg(2+)) channel (TRPM6), are exclusively expressed. This makes the DCT the major site of active transcellular Mg(2+) reabsorption determining the final excretion in the urine. Following the Mg(2+) influx via the apically localized TRPM6, intracellular Mg(2+) diffuses to the basolateral membrane where it is extruded to the blood compartment via still-unidentified Mg(2+) transporters. Recent years have witnessed multiple breakthroughs in the field of transcellular Mg(2+) reabsorption. Epidermal growth factor and estrogen were identified as magnesiotropic hormones by their effect on TRPM6 activity. Intracellularly, receptor of activated protein kinase C 1 and adenosine triphosphate were shown to inhibit TRPM6 activity through its alpha-kinase domain. Furthermore, dysregulation or malfunction of transcellular Mg(2+) reabsorption in DCT has been associated with renal Mg(2+) wasting. Mutations in TRPM6 are responsible for hypomagnesemia with secondary hypocalcemia. A defect in the gamma-subunit of the Na(+)/K(+)-adenosine triphosphatase causes isolated dominant hypomagnesemia resulting from renal Mg(2+) wasting. Moreover, in Gitelman's syndrome, mutations in NCC also result in impaired transcellular Mg(2+) reabsorption in DCT. This review highlights our recently obtained knowledge concerning the molecular regulation of transcellular Mg(2+) reabsorption.
Xi
Qi
Q
Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, The Netherlands.
Hoenderop
Joost G J
JG
Bindels
René J M
RJ
D000818:Animals; D004058:Diffusion; D004815:Epidermal Growth Factor / Q000235:genetics / Q000502:physiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007686:Kidney Tubules, Distal / Q000378:metabolism*; D008274:Magnesium / Q000097:blood / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D050053:TRPM Cation Channels / Q000378:metabolism*
D009363:Neoplasm Proteins; C419368:RACK1 protein, human; D000075370:Receptors for Activated C Kinase; D011956:Receptors, Cell Surface; D028021:Sodium-Potassium-Chloride Symporters; D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; D004815:Epidermal Growth Factor; D011494:Protein Kinases; D019204:GTP-Binding Proteins; D000254:Sodium-Potassium-Exchanging ATPase; D008274:Magnesium